Adverse reactions : תופעות לוואי

4.8     Undesirable effects
 a. Summary of the safety profile
The most frequent and common adverse reactions related to clarithromycin therapy for both adult and peadiatric populations are abdominal pain, diarrhoea, nausea, vomiting and taste perversion. These adverse reactions are usually mild in intensity and are consistent with the known safety profile of macrolide antibiotics (see section b of section 4.8).

There was no significant difference in the incidence of these gastrointestinal adverse reactions during clinical trials between the patient population with or without pre-existing mycobacterial infections.
 b. Tabulated summary of adverse reactions

The following table displays adverse reactions reported in clinical trials and from post-marketing experience with clarithromycin immediate-release tablets, granules for oral suspension, powder for solution for injection, extended- release tablets and modified-release tablets.

The reactions considered at least possibly related to clarithromycin are displayed by system organ class and frequency using the following convention: very common (≥1/10), common (≥ 1/100 to < 1/10), uncommon (≥1/1,000 to < 1/100) and not known (adverse reactions from post-marketing experience; cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness when the seriousness could be assessed.


System Organ     Very common      Common           Uncommon                    Not Known Class            ≥1/10            ≥ 1/100 to <     ≥1/1,000 to < 1/100         (cannot be estimated from 1/10                                         the available data)
Infections and                                     Cellulitis1, candidiasis,   Pseudomembranous colitis, infestations                                       gastroenteritis2,           erysipelas, erythrasma infection3, vaginal infection
Blood and                                          Leukopenia,                 Agranulocytosis, lymphatic                                          neutropenia4,               thrombocytopenia system                               thrombocythaemia3,
eosinophilia4
Immune system                        Anaphylactoid reaction1,     Anaphylactic reaction disorders5                           hypersensitivity
Metabolism and                       Anorexia, decreased          Hypoglycaemia6 nutrition                            appetite disorders
Psychiatric        Insomnia          Anxiety, nervousness3,       Psychotic disorder, disorders                            screaming3                   confusional state, depersonalisation,
depression, disorientation,
hallucination, abnormal dreams
Nervous system     Dysgeusia,        Loss of consciousness1,      Convulsion, ageusia, disorders          headache, taste   dyskinesia1, dizziness,      parosmia, anosmia perversion        somnolence7, tremor
Ear and                              Vertigo, hearing             Deafness labyrinth                            impaired, tinnitus disorders
Cardiac                              Cardiac arrest1, atrial      Torsade de pointes8, disorders                            fibrillation1,               ventricular tachycardia8 electrocardiogram QT prolonged8,
extrasystoles1,
palpitations
Vascular           Vasodilation1                                  Haemorrhage9 disorders
Respiratory,                         Asthma1, epistaxis2,
thoracic and                         pulmonary embolism1 mediastinal disorder
Gastrointestinal   Diarrhoea10,      Esophagitis1,                Pancreatitis acute, tongue disorders          vomiting,         gastrooesophageal reflux     discolouration, tooth dyspepsia,        disease2, gastritis,         discoloration nausea,           proctalgia2, stomatitis,
abdominal pain    glossitis, abdominal distension4, constipation,
dry mouth, eructation,
flatulence,
Hepatobiliary      Liver function    Cholestasis4, hepatitis4,    Hepatic failure11, jaundice disorders          test abnormal     alanine aminotransferase     hepatocellular increased, aspartate aminotransferase increased, gamma- glutamyltransferase increased4
Skin and           Rash,             Dermatitis bullous1,         Stevens-Johnson subcutaneous       hyperhidrosis     pruritus, urticaria, rash    syndrome5, toxic epidermal tissue disorders                     maculo-papular3              necrolysis5, drug rash with eosinophilia and systemic symptoms (DRESS), acne

Musculoskeletal                      Muscle spasms3,              Rhabdomyolysis2,12**, and connective                       musculoskeletal              myopathy tissue disorders                     stiffness1, myalgia2
Renal and                            Blood creatinine             Renal failure, nephritis urinary                              increased1, blood urea       interstitial disorders                                               increased1
General           Injection site     Injection site     Malaise4, pyrexia3, disorders and     phlebitis1         pain1, injection   asthenia, chest pain4, administration                       site               chills4, fatigue4 site conditions                      inflammation1
Investigations                                          Albumin globulin ratio   International normalised abnormal1, blood         ratio increased9,
alkaline phosphatase     prothrombin time increased4,              prolonged9, urine color blood lactate            abnormal dehydrogenase increased4

1
ADRs reported only for the Powder for Solution for Injection formulation 2
ADRs reported only for the Extended-Release Tablets formulation
3
ADRs reported only for the Granules for Oral Suspension formulation
4
ADRs reported only for the Immediate-Release Tablets formulation
5,8,10,11,12
See section a)
6,7,9
See section c)
 c. Description of selected adverse reactions

Injection site phlebitis, injection site pain, vessel puncture site pain, and injection site inflammation are specific to the clarithromycin intravenous formulation.

In very rare instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications (see section 4.4).

A special attention to diarrhoea should be paid as Clostridium difficile- associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents including clarithromycin, and may range in severity from mild diarrhoea to fatal colitis. (see section 4.4)

In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson Syndrome and toxic epidermal necrolysis, clarithromycin therapy should be discontinued immediately and appropriate treatment should be urgently initiated (see section 4.4).

As with other macrolides, QT prolongation, ventricular tachycardia, and torsade de pointes have rarely been reported with clarithromycin (see section        4.4 and 4.5).

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clarithromycin, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of antibacterial agents (see section 4.4).
In some of the reports of rhabdomyolysis, clarithromycin was administered concomitantly with statins, fibrates, colchicine or allopurinol (see section 4.3 and 4.4).
There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in elderly and/or patients with renal insufficiency, some with a fatal outcome. (see sections 4.4 and 4.5).

There have been rare reports of hypoglycaemia, some of which have occurred in patients on concomitant oral hypoglycaemic agents or insulin (see section 4.4 and 4.5).

There have been post-marketing reports of drug interactions and central nervous system (CNS) effects (e.g. somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested (see section 4.5).

There is a risk of serious haemorrhage and significant elevations in INR and prothrombin time when clarithromycin is co-administered with warfarin. INR and prothrombin times should be frequently monitored while patients are receiving clarithromycin and oral anticoagulants concurrently (see section 4.4 and 4.5).

There have been rare reports of clarithromycin ER tablets in the stool, many of which have occurred in patients with anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. In several reports, tablet residues have occurred in the context of diarrhoea. It is recommended that patients who experience tablet residue in the stool and no improvement in their condition should be switched to a different clarithromycin formulation (e.g. suspension) or another antibiotic.

Special population: Adverse Reactions in Immunocompromised Patients (see section e)
 d. Paediatric populations

Clinical trials have been conducted using clarithromycin paediatric suspension in children 6 months to 12 years of age. Therefore, children under 12 years of age should use clarithromycin paediatric suspension. There are insufficient data to recommend a dosage regimen for use of the clarithromycin IV formulation in patients less than 18 years of age.

Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.
 e. Other special populations

Immunocompromised patients
In AIDS and other immunocompromised patients treated with the higher doses of clarithromycin over long periods of time for mycobacterial infections, it was often difficult to distinguish adverse events possibly associated with clarithromycin administration from underlying signs of Human
Immunodeficiency Virus (HIV) disease or intercurrent illness.

In adult patients, the most frequently reported adverse reactions by patients treated with total daily doses of 1000 mg and 2000mg of clarithromycin were: nausea, vomiting, taste perversion, abdominal pain, diarrhoea, rash, flatulence, headache, constipation, hearing disturbance, Serum Glutamic Oxaloacetic Transaminase (SGOT) and Serum Glutamic Pyruvate Transaminase (SGPT) elevations. Additional low-frequency events included dyspnoea, insomnia and dry mouth. The incidences were comparable for patients treated with 1000mg and 2000mg, but were generally about 3 to 4 times as frequent for those patients who received total daily doses of 4000mg of clarithromycin.

In these immunocompromised patients, evaluations of laboratory values were made by analysing those values outside the seriously abnormal level (i.e. the extreme high or low limit) for the specified test. On the basis of these criteria, about 2% to 3% of those patients who received 1000mg or 2000mg of clarithromycin daily had seriously abnormal elevated levels of SGOT and SGPT, and abnormally low white blood cell and platelet counts. A lower percentage of patients in these two dosage groups also had elevated Blood Urea Nitrogen levels. Slightly higher incidences of abnormal values were noted for patients who received 4000mg daily for all parameters except White Blood Cell.